Understanding and Targeting Protein Synthesis in Leukemia Stem Cells
Abstract
Acute myeloid leukemia (AML) is a highly lethal blood cancer, where the majority of patients fail to respond to intensive chemotherapy or bone marrow transplant. Leukemia stem cells represent a rare subset of leukemia cells that are particularly resistant to chemotherapy and form a reservoir of cells that persist after treatment and are responsible for relapse. They do this in part by hijacking properties of normal blood stem cells, such as the ability to propagate themselves indefinitely (i.e., self-renewal). In fact, the more that leukemia stem cells gain this property, the more therapy-resistant AML becomes. Recent data has shown that normal blood stem cells maintain their ability to propagate the entire blood system through tight control of their rates of protein production. We believe that leukemia stem cells use this same mechanism to propagate AML; and in fact, our lab has identified a protein, called CD99, that may be responsible for controlling this mechanism in AML. Understanding how leukemia stem cells adopt such characteristics of normal blood stem cells to become more aggressive cancers is critical for us to cure the AMLs that are the hardest to treat. By studying these mechanisms, this project will address all three Rare Cancers Research Program Focus Areas by developing research models of AML to both better understand the etiology of AML, as well as to develop novel treatment strategies. In initial work, we have found that leukemia stem cells that most closely mimic normal blood stem cells do indeed depend more on a having tightly controlled rates of protein production. Such leukemia stem cells also give rise to the most aggressive AMLs. This suggests that therapies targeting mechanisms related to protein production may preferentially benefit AML patients who currently have the worst clinical outcomes. We have developed a novel strategy to disrupt protein production levels in leukemia stem cells in combination with a drug recently Food and Drug Administration-approved for the treatment of AML. We will test whether this strategy can overcome therapy resistance using a mouse model of AML that closely mimics AML cases with the worst clinical outcomes. Recognizing that there are many different types of AML, we will also perform our studies in mouse and human models of AML that are derived from the most common subtypes of AML. Because our studies disrupting protein synthesis will use drugs that have already been tested in the clinic for other purposes, if we identify promising drug combinations, they will be able to be tested in clinical trials in the immediate future. Finally, while leukemia stem cells may have highly suppressed levels of protein production, a small subset of proteins escape this suppression and are likely critical for their survival. We will identify these proteins, and in future studies that will extend beyond the timeframe of this award, we will test whether they may also be targeted to kill leukemia stem cells. In sum, our studies to better understand how AML is propagated through its control of protein production may ultimately lead to new strategies that can eradicate leukemia stem cells while sparing normal blood stem cells, allowing us to cure the most difficult-to-treat AMLs. The properties that we are studying in leukemia stem cells are also very likely to be shared by the stem cells that promote treatment resistance in many other malignancies, and thus this work has the potential to advance our ability to treat many rare cancers.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210857
Entities
People
- Stephen Chung
Organizations
- United States Army
- University of Texas Southwestern Medical Center